Project Summary Acute Kidney Injury (AKI) is common in hospitalized patients after severe illness or following major surgeries, such as cardiovascular surgery. The incidence of AKI in critically ill patients is greater than 40%. Patients who have an AKI event have poor long-term outcomes including increased debilitating comorbidities such as chronic kidney disease and increased mortality. Ischemia/reperfusion injury (IRI), an unavoidable consequence of cardiovascular surgery, is a known cause of AKI. IRI is partially the result of the formation of reactive oxygen species (ROS) in the absence of sufficient antioxidative moieties, and can lead to the induction of inflammation. There is currently no clinically available therapeutic treatment to prevent or treat AKI, which leaves a large cohort of suffering patients and a high burden on our healthcare system. Our product, APP-103?, consists of effective anti-oxidant and anti-inflammatory copolymer nanoparticles that have previously been demonstrated to be highly effective in ameliorating damage from oxidative stress in several IRI models of kidney, heart, limb injury, and renal transplantation. APP-103? is a dispersion of polyoxalate-vanillyl alcohol (VA) copolymer particles that is degraded by hydrogen peroxide, thereby reducing the local concentration of ROS and yielding anti-inflammatory VA. The polymer chemistry and biology of APP-103 is well understood and indicative of an excellent safety profile. While easily administered systemically, it offers site-specific anti-oxidative and anti-inflammatory therapy without expensive and marginally effective targeting molecules. A single 500 nm diameter APP? particle provides the ability to mitigate ~1011 ROS molecules, and is activated only in the presence of ROS, i.e. APP activity is self-limiting. To date, we have been able to produce APP-103? at the scale necessary for preclinical work, and are advancing through IND-enabling studies with no toxicity. We have also demonstrated efficacy in pre-clinical AKI models. The purpose of this proposal is to provide mechanistic insight of APP-103 in kidney IRI, demonstrate proof of concept in a large animal model of AKI, and then advance APP-103? from lab manufacturing through completion of IND-enabling studies. The milestone of ultimate success will be the submission of an IND in order to bring this exceptionally promising therapy into clinical application.